Early childhood neurodevelopmental milestones in children with allergic diseases: the Japan Environment and Children’s Study (JECS)

This study investigated the potential link between early childhood allergic diseases and neurodevelopmental milestone attainment during the first 3 years of life. Utilizing data from a large-scale prospective birth cohort study in Japan, encompassing 87,986 children, we examined physician-diagnosed and caregiver-reported allergic conditions, including atopic dermatitis (AD), asthma, and food allergy (FA). Neurodevelopmental milestones were assessed using the Ages and Stages Questionnaires at 1, 1.5, 2, 2.5, and 3 years of age. Stabilized inverse probability-weighted generalized estimating equation models were employed to estimate odds ratios (ORs). Our analysis revealed no significant association of AD and asthma with delay in communication, gross motor, fine motor, problem-solving, and personal-social skills during the initial 3 years of life. However, children with FA showed an increased likelihood of experiencing gross motor delay compared with that shown by those without FA (weighted adjusted OR: 1.14). Despite this, no significant association of FA with other developmental domains was observed. Early childhood allergies may not influence neurodevelopmental delays. However, there is a potential association between FA and delays, specifically in gross motor skills, that warrants routine developmental monitoring and additional investigations.


List of Contents
• Methods: Supplementary Methods • Table 1.Frequencies of suspected developmental delay in ASQ-3 milestones (n = 87986) • Table 2. Frequencies of suspected neurodevelopmental delay in ASQ-3 milestones according to the early childhood allergic disorders • Table 3. Association of ISAAC-based eczema/AD and wheezing features with ASQ-3 developmental milestones • Table 4. Sensitivity analysis of the association of allergic diseases with ASQ-3 developmental milestones in trimmed stabilized weighted generalized estimating equations (GEEs) models • Table 5. Sensitivity analysis of the association of allergic diseases with ASQ-3 developmental milestones in GEE models with multiple imputation • Table 6.Sensitivity analysis of the association of allergic diseases with ASQ-3 developmental milestones in GEE models, excluding ASQ-3 missing values (n = 53,364) • Table 7. Sensitivity analysis of the association of allergic diseases with ASQ-3 developmental milestones with sample mean -(2 × standard deviation [SD]) as cutoff values for each J-ASQ-3 domain • Table 8.Association of allergic comorbidities with ASQ-3 developmental milestones.
• Table 9. Subgroup analysis by child's sex for the association of early childhood allergic diseases with ASQ-3 developmental milestones

Figure 1 .
Figure 1.Directed acyclic graph for the association between early childhood allergic diseases and neurodevelopment Directed acyclic graphs depict the hypothesized potential confounding factors (red nodes) in the association between early childhood allergic diseases and neurodevelopment.Blue nodes: variables associated with neurodevelopment in the offspring.Mediators are not included.PSEDS, parental socioeconomic and demographic status (maternal age, marital status, maternal and paternal education, and annual household income); PPSF, parental psychosocial factors (maternal and paternal smoking and maternal alcohol consumption during pregnancy); BMI, body mass index (prepregnancy); DM; diabetes mellitus; MPD, maternal psychological distress during pregnancy; maternal pre-pregnancy history of allergic diseases; atopic dermatitis, asthma, and food allergy; supplements during pregnancy: iron pill and folic acid.

Table 12 .
Characteristics of the attained stabilized weights •

Table 13 .
Covariate balance between allergic and non-allergic groups • Figure 1.Directed acyclic graph for the association between early childhood allergic diseases and neurodevelopment • References

Table 1 .
Frequencies of suspected developmental delay in ASQ-3 milestones (n = 87,986) Ages and Stages Questionnaires, third edition Child neurodevelopment was assessed using a total score in each domain that fell less than 2 SDs below the mean in the reference, denoted as either typical or potentially delayed.The cutoff values for ASQ-3 are detailed in Table11.

Table 2 .
Frequencies of suspected neurodevelopmental delay in ASQ-3 milestones according to the early childhood allergic diseases

Table 3 .
Association of ISAAC-based eczema/AD and wheezing features with ASQ-3 developmental milestones

domains, weighted AOR (95% CI) a Eczema/AD b Communication skills Gross Motor skills Fine Motor skills Problem-solving skills
International Study of Asthma and Allergies in Childhood; AOR, adjusted odds ratio; CI, confidence interval; ASQ-3, Ages and Stages Questionnaires, third edition.a Weighted AOR were derived via propensity score based, logistic regression models.
bAdjusted for wheezing features.c Adjusted for eczema/AD features

Table 4 .
Sensitivity analysis of the association of allergic diseases with ASQ-3 developmental milestones in trimmed stabilized weighted generalized estimating equations (GEEs) models a Weighted AOR was derived via propensity score-based, stabilized inverse probability weighted GEE models.b

Table 5 .
Sensitivity analysis of the association of allergic diseases with ASQ-3 developmental milestones in GEE models with multiple imputation AOR, adjusted odds ratio; CI, confidence interval; ASQ-3, Ages and Stages Questionnaires, third edition.aWeighted AOR was derived via propensity score-based, stabilized inverse probability weighted GEE models.b adjusted for asthma and food allergy c adjusted for atopic dermatitis and food allergy d adjusted for asthma and atopic dermatitis e p<0.001

Table 6 .
Sensitivity analysis of the association of allergic diseases with ASQ-3 developmental milestones in GEE models, excluding missing ASQ-3 values (n = 53,364) AOR, adjusted odds ratio; CI, confidence interval; ASQ-3, Ages and Stages Questionnaires, third edition.aWeighted AOR was derived via propensity score-based, stabilized inverse probability weighted GEE models.b adjusted for asthma and food allergy c adjusted for atopic dermatitis and food allergy d adjusted for asthma and atopic dermatitis e p<0.01

Table 8 .
Association of allergic comorbidities with ASQ-3 developmental milestones AOR was obtained via generalized estimating equations models (adjusted for maternal age at delivery, marital status, pre-pregnancy body mass index, gestational diabetes, infertility treatment, psychological distress, iron and folic acid supplementation, pre-pregnancy history of AD, asthma, FA, alcohol consumption, maternal and paternal formal education, smoking during pregnancy, household income, mode of delivery, child's sex, gestational age, birth weight, breastfeeding, formula feeding, and child's nursery attendance) b Participants with no reported allergic conditions at any survey point.

Table 9 .
Subgroup analysis by child's sex for the association of early childhood allergic diseases with ASQ-3 developmental milestones

Table 12 .
Characteristics of the attained stabilized weights

Table 13 .
Covariate balance between allergic and non-allergic groups